Why is oral cancer screening important

Thrombosis and cancer: prophylaxis and therapy

Tumor patients with a thrombosis have a worse chance of survival than cancer patients without such an event. However, routine thrombosis prophylaxis for all tumor patients is not recommended.

Photo: Science Photo Library / Steve Gschmeissner

The connection between tumor diseases and thrombosis was medically described for the first time over 150 years ago. Thromboses are the most common and dangerous complications for cancer patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE), summarized under the term venous thromboembolism (s) (VTEs), as well as thrombosis of the superficial cutaneous veins (superficial venous thrombosis; OVT) occur frequently in tumor patients (1–5). They worsen their prognosis, are a major cause of mortality, complicate therapy, and impair quality of life (6, 7). Antithrombotic therapy also increases the risk of bleeding associated with malignancy. The prophylaxis and therapy of thromboembolism in tumor patients differ in essential aspects from the procedure in non-tumor patients.

About 20% of all VTEs occur in cancer patients; conversely, about 20% of all cancer patients develop VTEs in the course of their disease (2, 8). Due to the changing age structure and the increasing life expectancy of cancer patients, a relative and absolute increase in VTEs in cancer patients is to be expected.

The risk of VTEs is about 4 to 7 times higher than that of non-tumor patients, with a large variance depending on tumor entity and stage (9) as well as patient- and treatment-dependent factors (Figure 1). These relationships should be pointed out and cancer patients should be informed about the first symptoms of VTE.

Risk factors for the development of venous thromboembolism (s) in tumor patients (modified from [9])

In the case of VTEs without recognizable evidence of a triggering event, the presence of a paraneoplastic thrombosis should be considered; the risk of malignancy in the following months is about 1½ to 2 times higher than in individuals without VTE (10). Even if there is no evidence of an underlying cancer, the implementation of age- and gender-specific preventive examinations should be encouraged (11).

Prophylaxis in cancer patients

Hospital stays, operations, central (venous) indwelling catheters, drug tumor therapies and others (Figure 1) increase the individual risk of venous thromboembolism. The guidelines therefore recommend high-risk VTE prophylaxis for:

  • hospitalized surgical tumor patients (usually for 4–5 weeks postoperatively)
  • and - on a limited database - also for non-surgical tumor patients in hospitals, taking into account mobility and contraindications.

In cancer patients treated on an outpatient basis, the indication for primary drug-based VTE prophylaxis must be made individually, especially in patients with pancreatic, gastric or lung cancer (12).

Diagnosis

Cancer patients often complain of symptoms associated with the underlying disease or therapy, which can also be caused by a venous thromboembolism. It is not uncommon for "incident" VTEs to be discovered for the first time during tumor progression examinations.

The clinical symptoms of a superficial vein thrombosis with spontaneous or tender inflammation along the indurated course of a superficial cutaneous vein are usually unambiguous. To determine the extent of the thrombosis and to rule out a (often simultaneous) deep vein thrombosis in the area of ​​the ipsi- or contralateral lower extremity, a Doppler sonographic diagnosis should be performed here (11).

In contrast to non-tumor patients, the determination of the D-dimer value - with a high negative predictivity if the test result is in the reference range - is usually not helpful, since increased D-dimer values ​​can be assumed if the disease is known to be manifest.

According to the guideline algorithm of the AWMF (11), an objectifying diagnosis by means of compression or duplex sonography or, in the case of PE suspicion, by means of modern contrast-enhanced computed tomography (multislice CT) must be carried out immediately in tumor patients.

OVT therapy in cancer patients

There are no specific studies for the treatment of superficial vein thrombosis in cancer patients. Long-term anticoagulation with 2.5 mg fondaparinux for 45 days, supplemented by local compression and non-steroidal anti-inflammatory medication, is the best-documented therapy of choice (13, 14).

If the clinical symptoms do not recede rapidly after the initiation of anticoagulation therapy or even persist for weeks, then (after excluding the progression to DVT), prolonging the anticoagulation and / or intensifying the therapy should be considered.

Initial therapy / secondary prophylaxis

Acute therapeutic anticoagulation with LMWH for tumor-associated VTE (cancer-associated thrombosis, CAT), supported by symptom-adapted external compression treatment, is intended to prevent the progression of thrombosis or the occurrence of pulmonary embolism and alleviate acute symptoms (11). This makes it possible to reduce CAT-associated mortality and the morbidity - which is often more pronounced in tumor patients - and to maintain or restore the quality of life of those affected.

Meta-analyzes of the initial therapy (1–2 weeks) show a higher efficacy, fewer bleeding complications and a reduction in 3-month mortality for the - mostly outpatient - therapy with low molecular weight heparin (LMWH) compared to unfractionated heparin (15).

In contrast to the procedure for non-tumor patients, the consensus guidelines recommend continuing therapeutic anticoagulation for CAT with LMWH for (3–) 6 months (11, 16).

The main reasons for this are 2 larger (CLOT, CATCH) and a few smaller studies and their meta-analysis, which show that continued therapeutic anticoagulation with LMWH compared to an oral vitamin K antagonist (target INR 2–3) With a comparable bleeding risk, VTE recurrences can be halved (Figure 2) (17).

Meta-analysis of 3 to 6 months of anticoagulation with LMWH compared to standard therapy with LMWH, followed by VKA (modified from [17])

Nevertheless, in 5–10% of tumor patients, VTE recurrences occur preferentially in the first 3 months. In these patients, the dose of LMWH should be escalated by 20–30% without laboratory monitoring (18). As with the initial therapy for acute CAT, the clinical result should be checked and examined for signs of bleeding in the first few days after the dose increase (11).

The use of oral anticoagulants should only be considered if there are contraindications for LMWH (e.g. heparin-induced thrombocytopenia type 2) and subcutaneous applications cannot be carried out (e.g. if the patient refuses it) (11, 6).

The non-vitamin K-dependent oral anticoagulants (NOACs) approved in addition to the vitamin K antagonists for the treatment of VTE in recent years have shown in large approval studies - with preparation-specific differences - compared to standard therapy (LMWH → VKA [Ziel-INR 2–3]) a comparable effectiveness with a reduced risk of severe bleeding complications (19). Patients with overt tumor disease and active (chemotherapeutic) treatment were not included in most of these studies, or only very rarely.

The available subgroup analyzes of - inadequately characterized "lighter" - tumor patients confirm old results, which showed an increased risk of VTE recurrence and bleeding in tumor patients compared to non-tumor patients.

The fact that the tumor patients in these studies were “less ill” is also shown in the lower mortality and the better quality of the VKA therapy compared to the patients in the CLOT and CATCH studies.

A meta-analysis of the “tumor patients with acute VTE” included in the NOAC studies shows that the efficacy of the standard therapy arm (LMWH → VKA) is comparable with a possibly reduced risk of bleeding (20).

The first results of prospective randomized studies examining NOAC with guideline-compliant therapy using LMWH in CAT are expected in the next few weeks.

How long to anticoagulate?

In many tumor patients with venous thromboembolism, the risk factor "active tumor disease" persists even after 3 to 6 months of anticoagulation, so that in these cases, based on a lower level of evidence, a longer-term continuation of anticoagulation is recommended, with priority given to the risk of bleeding.

Based on the individual experience of several months of LMWH therapy oncological patients, an individual risk-benefit assessment is then recommended, including the type, dynamics and treatment of the malignancy, mobility, morphological findings (thrombus regression), laboratory values ​​(C. -reactive protein, D-dimer, etc.), but in particular patient preference should also be included.

Prospective data on prolonged anticoagulation beyond 6 months are only available for LMWH (21, 22), but without comparison with other anticoagulants.

Therefore, in addition to continuing anticoagulation with LMWH, oral therapy with NOACs or VKA can also be considered individually (11). ▄

DOI: 10.3238 / PersOnko / 2017.12.01.01

Dr. med. Piet Habbel,

Prof. Dr. med. Hanno Riess

Medical clinic with a focus on hematology,
Oncology and Tumor Immunology, Charité, Universitätsmedizin Berlin

Conflict of interest statement: Prof. Riess reports consulting fees from Aspen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Leo Pharma and Pfizer. Dr. Habbel declares that there is no conflict of interest.

Literature on the Internet:
www.aerzteblatt.de/lit4817

Causes of thrombosis in cancer patients

Both venous thromboembolism and tumor diseases increase with advancing age. In addition, malignant diseases trigger acute phase reactions which, by activating the complement and coagulation cascade, contribute to an increased risk of thrombosis.

In relation to Virchow’s triad, the acute phase reaction changes the blood composition in tumor patients: high fibrinogen, high factor VIII values, high leukocyte and platelet counts increase the tendency to clot. It is not uncommon for tumors to compress the blood vessels.

Ovarian cancer, for example, presses on the pelvic vein and obstructs the vein flow, or the biliary tumor presses on the portal vein and impairs the portal vein flow. The stasis favors the development of a thrombosis. Damage to the vascular wall also occurs if, for example, a tumor infiltrates a vessel or tumor-associated cytokines damage the endothelium.

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